Revisión
Genes y moléculas implicados en la virulencia de Aspergillus fumigatusGenes and molecules involved in Aspergillus fumigatus virulence

https://doi.org/10.1016/S1130-1406(05)70001-2Get rights and content

Resumen

Aspergillus fumigatus causa enfermedades muy variadas que incluyen micotoxicosis, reacciones alérgicas y enfermedades sistémicas con altas tasas de mortalidad (aspergilosis invasoras; AI). La patogenicidad parece depender del estado inmune del paciente pero también del aislamiento fúngico. No parece existir un verdadero factor de virulencia único y esencial para el desarrollo de este hongo en el paciente y la virulencia de A. fumigatus parece ser poligénica. Entre las moléculas y los genes que se han relacionado con la virulencia de este hongo se encuentran componentes de la pared celular como ß(1-3)-glucano, galactomanano, galactomanoproteínas (Afmp1 y Afmp2), y enzimas quitina sintetasas (Chs; chsE y chsG), entre otras. Algunos genes y moléculas se han relacionado con la evasión de la respuesta inmune, como la capa rodlets, (gen rodA/hyp1) y la melanina-DHN (gen pksP/alb1) de los conidios. También los sistemas de detoxificación de los compuestos derivados del oxígeno (ROS) por parte de catalasas (Cat1p y Cat2p) y superoxidodismutasas (MnSOD y Cu,ZnSOD) entre otras, se han apuntado con frecuencia como esenciales en su virulencia. Así mismo, este hongo produce toxinas (la sustancia difusible de los conidios de 14 kDa, fumigaclavina C, aurasperona C, gliotoxina, ácido helvólico, fumagilina, Asp-hemolisina y la ribotoxina Asp fI/mitogilina F/restrictocina), alérgenos (Asp f1 a Asp f23) y proteínas enzimáticas como serina proteasas alcalinas (Alp y Alp2), metaloproteasas (Mep), aspártico proteasas (Pep y Pep2), dipeptidilpeptidasas (DppIV y DppV), fosfolipasa C y fosfolipasa B (Plb1 y Plb2). Estas sustancias tóxicas y enzimas parecen actuar de forma aditiva y/o sinérgica reduciendo la supervivencia de los animales infectados, bien por afección directa de las células del huésped o bien por favorecer la penetración del microorganismo durante la infección. La capacidad de adaptarse a los cambios a distintas condiciones tróficas es un atributo esencial de muchos patógenos. En el caso de la virulencia de A. fumigatus se han apuntado como necesarias las siguientes capacidades y reacciones: obtención de hierro mediante sideróforos de tipo hidroxamato (ornitina monooxigenasa/SidA), obtención de fósforo (fos1, fos2 y fos3), cascadas de transducción de señales que regulan la morfogénesis y/o la utilización de nutrientes como el nitrógeno (rasA, rasB, rhbA), quinasas activadas por mitógenos (MAP-quinasa codificada por el gen sakA), ruta de señales de transducción de AMPc-Pka, y otras. Parecen ser también esenciales en este campo la biosíntesis de aminoácidos (cpcA y homoaconitasa/lysF), la activación y expresión de algunos genes a una temperatura de 37 °C (Hsp1/Asp f12, cgrA), las moléculas y genes que mantienen la viabilidad celular de A. fumigatus (smcA, Prp8, anexinas), etc. Por otro lado, en los últimos tiempos, el conocimiento de la relación entre este patógeno y la respuesta inmune del huésped ha sido mejorada, y se abren nuevas vías de investigación. Se ha detectado la participación en la infección tanto de células no profesionales (endoteliales, epiteliales traqueales y alveolares) como profesionales (células asesinas naturales o NK y células dendríticas). Los patrones moleculares asociados al patógeno (PAMP) y los receptores que reconocen esos patrones (PRR; como por ejemplo receptors de tipo Toll TLR-2 y TLR-4), pueden influir en la respuesta inflamatoria y el perfil de citoquinas dominante, y por tanto en la respuesta Th contra la infección. Los componentes superficiales del hongo y los receptores de las células del huésped que parecen dirigir estos fenómenos, son todavía desconocidos, aunque pudieran estar implicadas algunas de las moléculas ya asociadas con la virulencia. La secuenciación del genoma de A. fumigatus y el estudio de la expresión de genes durante los procesos infecciosos de este hongo mediante el uso de microarray y biochips de ADN, permitirán en un futuro no muy lejano ampliar los conocimientos sobre la virulencia de este hongo.

Summary

Aspergillus fumigatus causes a wide range of diseases that include mycotoxicosis, allergic reactions and systemic diseases (invasive aspergillosis) with high mortality rates. Pathogenicity depends on immune status of patients and fungal strain. There is no unique essential virulence factor for development of this fungus in the patient and its virulence appears to be under polygenetic control. The group of molecules and genes associated with the virulence of this fungus includes many cell wall components, such as ß(1-3)-glucan, galactomannan, galactomannanproteins (Afmp1 and Afmp2), and the chitin synthetases (Chs; chsE and chsG), as well as others. Some genes and molecules have been implicated in evasion from the immune response, such as the rodlets layer (rodA/hyp1 gene) and the conidial melanin-DHN (pksP/alb1 gene). The detoxifying systems for Reactive Oxygen Species (ROS) by catalases (Cat1p and Cat2p) and superoxide dismutases (MnSOD and Cu,ZnSOD), had also been pointed out as essential for virulence. In addition, this fungus produces toxins (14 kDa diffusible substance from conidia, fumigaclavin C, aurasperon C, gliotoxin, helvolic acid, fumagilin, Asp-hemolysin, and ribotoxin Asp fI/mitogilin F/restrictocin), allergens (Asp f1 to Asp f23), and enzymatic proteins as alkaline serin proteases (Alp and Alp2), metalloproteases (Mep), aspartic proteases (Pep and Pep2), dipeptidyl-peptidases (DppIV and DppV), phospholipase C and phospholipase B (Plb1 and Plb2). These toxic substances and enzymes seems to be additive and/or synergistic, decreasing the survival rates of the infected animals due to their direct action on cells or supporting microbial invasion during infection. Adaptation ability to different trophic situations is an essential attribute of most pathogens. To maintain its virulence attributes A. fumigatus requires iron obtaining by hydroxamate type siderophores (ornitin monooxigenase/SidA), phosphorous obtaining (fos1, fos2, and fos3), signal transductional falls that regulate morphogenesis and/or usage of nutrients as nitrogen (rasA, rasB, rhbA), mitogen activated kinases (sakA codified MAP-kinase), AMPc-Pka signal transductional route, as well as others. In addition, they seem to be essential in this field the amino acid biosynthesis (cpcA and homoaconitase/lysF), the activation and expression of some genes at 37 °C (Hsp1/Asp f12, cgrA), some molecules and genes that maintain cellular viability (smcA, Prp8, anexins), etc. Conversely, knowledge about relationship between pathogen and immune response of the host has been improved, opening new research possibilities. The involvement of non-professional cells (endothelial, and tracheal and alveolar epithelial cells) and professional cells (natural killer or NK, and dendritic cells) in infection has been also observed. Pathogen Associated Molecular Patterns (PAMP) and Patterns Recognizing Receptors (PRR; as Toll like receptors TLR-2 and TLR-4) could influence inflammatory response and dominant cytokine profile, and consequently Th response to infection. Superficial components of fungus and host cell surface receptors driving these phenomena are still unknown, although some molecules already associated with its virulence could also be involved. Sequencing of A. fumigatus genome and study of gene expression during their infective process by using DNA microarray and biochips, promises to improve the knowledge of virulence of this fungus.

Bibliografía (213)

  • J.R. Fortwendel et al.

    Aspergillus fumigatus rasA and rasB regulate the timing and morphology of asexual development

    Fungal Genet Biol

    (2004)
  • M. Fox et al.

    Detection of Aspergillus fumigatus mycotoxins: immunogen synthesis and immunoassay development

    J Microbiol Methods

    (2004)
  • I. Fujii et al.

    Hydrolytic polyketide shortening by ayg1p, a novel enzyme involved in fungal melanin biosynthesis

    J Biol Chem

    (2004)
  • Y. Fukuchi et al.

    Oxidized low density lipoprotein inhibits the hemolytic activity of Asphemolysin from Aspergillus fumigatus

    FEMS Microbiol Lett

    (1998)
  • M.E. García et al.

    Evaluation of molecular and immunological techniques for the diagnosis of mammary aspergillosis in ewes

    Vet Microbiol

    (2004)
  • H. Hebart et al.

    Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies

    Blood

    (2002)
  • K. Ishibashi et al.

    The solubilization and biological activities of Aspergillus beta-(1->3)-D-glucan

    FEMS Immunol Med Microbiol

    (2004)
  • R. Kao et al.

    Molecular dissection of mitogillin reveals that the fungal ribotoxins are a family of natural genetically engineered ribonucleases

    J Biol Chem

    (1999)
  • M.M. Kessler et al.

    The use of direct cDNA selection to rapidly and effectively identify genes in the fungus Aspergillus fumigatus

    Fungal Genet Biol

    (2002)
  • V. Khalaj et al.

    Identification of a novel class of annexin genes

    FEBS Lett

    (2004)
  • Y. Kudo et al.

    Oxidized low-density lipoprotein-binding specificity of Asp-hemolysin from Aspergillus fumigatus

    Biochim Biophys Acta

    (2001)
  • A. Kumar et al.

    Isolation and characterization of a recombinant heat shock protein of Aspergillus fumigatus

    J Allergy Clin Immunol

    (1993)
  • V.P. Kurup et al.

    Respiratory fungal allergy

    Microbes Infect

    (2000)
  • K. Langfelder et al.

    Biosynthesis of fungal melanins and their importance for human pathogenic fungi

    Fungal Genet Biol

    (2003)
  • M.L. Abarca

    Taxonomía e identificación de especies implicadas en la aspergilosis nosocomial

    Rev Iberoam Micol

    (2000)
  • M.J. Allen et al.

    Binding of rat and human surfactant proteins A and D to Aspergillus fumigatus conidia

    Infect Immun

    (1999)
  • M.J. Allen et al.

    Interactions of surfactant proteins A and D with Saccharomyces cerevisiae and Aspergillus fumigatus

    Infect Immun

    (2001)
  • R. Amitani et al.

    Purification and characterization of factors produced by Aspergillus fumigatus which affect human ciliated respiratory epithelium

    Infect Immun

    (1995)
  • U. Appenzeller et al.

    IgE-mediated reactions to autoantigens in allergic diseases

    Int Arch Allergy Immunol

    (1999)
  • R. Araujo et al.

    Variability of germinative potential among pathogenic species of Aspergillus

    J Clin Microbiol

    (2004)
  • L.K. Arruda et al.

    Selective expression of a major allergen and cytotoxin, Asp f I, in Aspergillus fumigatus. Implications for the immunopathogenesis of Aspergillusrelated diseases

    J Immunol

    (1992)
  • A. Aufauvre-Brown et al.

    Comparison of virulence between clinical and environmental isolates of Aspergillus fumigatus

    Eur J Clin Microbiol Infect Dis

    (1998)
  • B. Banerjee et al.

    Molecular biology of Aspergillus allergens

    Front Biosci

    (2003)
  • B. Banerjee et al.

    Cloning and expression of Aspergillus fumigatus allergen Asp f 16 mediating both humoral and cell-mediated immunity in allergic bronchopulmonary aspergillosis (ABPA)

    Clin Exp Allergy

    (2001)
  • B. Banerjee et al.

    C-terminal cysteine residues determine the IgE binding of Aspergillus fumigatus allergen Aspf2

    J Immunol

    (2002)
  • A. Beauvais et al.

    Glucan synthase complex of Aspergillus fumigatus

    J Bacteriol

    (2001)
  • A. Beauvais et al.

    Dipeptidyl-peptidase IV secreted by Aspergillus fumigatus, a fungus pathogenic to humans

    Infect Immun

    (1997)
  • S. Bellocchio et al.

    The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo

    J Immunol

    (2004)
  • S. Bellocchio et al.

    TLRs govern neutrophil activity in aspergillosis

    J Immunol

    (2004)
  • M. Bernard et al.

    Aspergillus fumigatus cell wall: composition and biosynthesis

    Med Mycol

    (2001)
  • M. Bernard et al.

    Characterization of a cell-wall acid phosphatase (PhoAp) in Aspergillus fumigatus

    Microbiology

    (2002)
  • R. Bhabhra et al.

    Disruption of the Aspergillus fumigatus gene encoding nucleolar protein CgrA impairs thermotolerant growth and reduces virulence

    Infect Immun

    (2004)
  • M. Birch et al.

    Comparison of extracellular phospholipase activities in clinical and environmental Aspergillus fumigatus isolates

    Med Mycol

    (2004)
  • M. Birch et al.

    Evidence of multiple extracellular phospholipase activities of Aspergillus fumigatus

    Infect Immun

    (1996)
  • J.L. Blanco et al.

    Correlation between the elastase activity index and invasiveness of clinical isolates of Aspergillus fumigatus

    J Clin Microbiol

    (2002)
  • D. Boettner et al.

    Molecular cloning of Aspergillus fumigatus CgrA, the ortholog of a conserved fungal nucleolar protein

    Med Mycol

    (2001)
  • S. Braedel et al.

    Aspergillus fumigatus antigens activate innate immune cells via toll-like receptors 2 and 4

    Br J Haematol

    (2004)
  • A.A. Brakhage et al.

    Menacing mold: the molecular biology of Aspergillus fumigatus

    Annu Rev Microbiol

    (2002)
  • A.A. Brakhage et al.

    Pigment biosynthesis and virulence

    Contrib Microbiol

    (1999)
  • J.S. Brown et al.

    Signature-tagged and directed mutagenesis identify PABA synthetase as essential for Aspergillus fumigatus pathogenicity

    Mol Microbiol

    (2000)
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